1. Field of the Invention
This invention relates to a method of making a sterile biodegradable polymeric implant in which polymerization takes place in a mold, and to the implants produced therefrom.
2. Description of the Prior Art
In 1998, a National Health Interview Survey estimated that 32 million musculoskeletal injuries are reported in the United States each year. Surgical operations are required for more than 3 million cases with almost 40% involving fracture fixation or arthroplasties. Of those patients with an implanted fixation device, there are a great number of reported problems.
There are a large number of synthetic materials that are classified as bone repair devices used to initiate bone regeneration. Currently, the preferred materials used to initiate bone regeneration are metals, including stainless steel and titanium alloys. The strength, durability, shortened healing time, and exact repositioning of the fractured bone associated with these devices are among the greatest advantages. In the initial stages of healing, the high stiffness of the metals is preferred for the rigid fixation of the fracture. Unfortuantely, the continued stiffness throughout healing may impede bone remodelling. Additionally, other undesirable factors, including xe2x80x9cstress-shielding,xe2x80x9d sensitization, corrosion and implant removal, related to the use of metallic materials have led to continued research for more suitable materials.
Biodegradable polymers have been considered in a variety of medical applications. Biodegradable polymers have proved successful as fracture fixation devices (implants), as well as suture materials, cardiovascular devices and drug delivery systems.
Traditional methods of preparing polymers, whether or not used as implantation devices, include bulk or melt polymerization, and solution polymerization. A polymer made by these processes must then be formed into the final usable product by a conventional molding technique, such as injection molding, compression molding or extrusion followed by sterilization. There are a number of problems associated with conventional manufacturing and sterilization processes of biodegradable polymers. These generally center around decreases in molecular weight of the polymer (which equates to a decrease in the mechanical strength) and the introduction of toxic substances (such as processing solvents and sterilization reagents) into a mammalian body.
One method of producing biodegradable implants is melt processing. For example, Bezwada et al., U.S. Pat. No. 5,470,340, discloses surgical devices made from copolymers of p-dioxanone and a prepolymer of p-dioxanone and a lactide or glycolide. The surgical devices are formed by conventional melt processing techniques. Additionally, Bezwada et al., U.S. Pat. No. 5,037,950 discloses bioabsorbable sutures and coatings for sutures made from copolymers of polyalkylene carbonate and xcfx81-dioxanone.
Melt processing involves extrusion or injection molding at high temperatures, introducing the possibility of thermal degradation and a subsequent reduction in the molecular weight of the polymer. Also, the crystallinity of the polymer, which directly impacts the mechanical properties of the device, is lost during melt processing and must be reformed to the desired degree by post injection processes that can be very difficult to control. Additionally, the melt viscosity of the polymer is proportional to the molecular weight of the polymer, making it very difficult to manufacture high molecular weight parts with detailed or complex geometry by melt processing.
Most biodegradable polymers can also be processed by solution processing. The low temperatures associated with this method eliminates the threat of thermal degradation. However, residual solvent could be toxic and elicit unfavorable tissue responses. Also, only fibers and films can normally be made by this technique. Bendix et al., U.S. Pat. No. 4,810,775, discloses a method of purifying resorbable polymers by solution processing. The purified polymers are used for medicinal purposes and are formed into their objects of use by compression molding.
Gel casting processes were developed to produce biological polymeric implants based on the principles used in solution processing. The polymer is dissolved in a solvent and cast into a mold allowing gel formation. The polymer is then removed from the mold and dried to obtain the solid implant. However, complete extraction of the solvent must be attained to ensure no toxins are introduced into the mammalian body in which the implant is implanted. Gogolewski et al., U.S. Pat. No. 5,275,601, discloses resorbable polymer bone screws and bone plates made from polyhydroxyacids, including polylactides. The implant devices are made by injection molding, compression molding, extrusion and/or gel processing the polymer. Similarly, Coombes et al., U.S. Pat. No. 5,397,572, discloses biodegradable implantation devices made from gelling a solution of a single polylactide enantiomer. The devices are made by dissolving the polymer in a solvent, casting the dissolved polymer in a mold, forming a gel in situ, removing the gel from the mold, and drying to obtain the solid implantation device. Boyan et al., U.S. Pat. No. 5,492,697, discloses the same process for making biodegradable implants of polylactic acid-polyglycolic acid copolymers.
A further technique developed for preparing polymers is reaction injection molding. Reaction injection molding has been used to form a number of different objects from a number of different polymers. For example, Beshouri et al., U.S. Pat. No. 5,349,046, discloses using reaction injection molding techniques to form xcex2-lactone polymers useful as automotive parts, housewares, appliances, electrical components and sporting goods. About 60-85% of the polymerization takes place in the mold.
Similarly, Rhodes et al., U.S. Pat. No. 5,668,234, discloses using reaction injection molding techniques to form polymers of methyl methacrylates, lactams, lactones or acrylamides, useful for sanitary or bathroom items, such as sinks, bathtubs, shower stalls, tabletops and the like. About 90-95% of the polymerization takes place in the mold.
Further, Zdrahala et al., U.S. Pat. No. 4,190,711, discloses using reaction injection molding techniques to form thermoplastic polyether polyurethane elastomers useful in the production of automotive body panels, gears, seals and the like. Noritake et al., U. S. Pat. No. 5,514,322, discloses using reaction injection molding techniques for forming thermoplastic resins of lactams, lactones and carbonates.
Grigpma et al., U.S. Pat. No. 5,492,997, discloses the possibility of using reaction injection molding techniques to form biological medical implants consisting of copolymers of lactone and cyclic carbonate.
Conventional methods of sterilizing a biodegradable implant include treating with ethylene oxide or exposing to ionizing radiation. Such methods are used prior to the implant being implanted into a mammalian body. Sterilization processes can affect the performance of a biodegradable implant. Changes in both molecular weight and mechanical properties are observed with current sterilization techniques.
Most biodegradable implants are sterilized by an ethylene oxide treatment. Jamiolkowski et al., U.S. Pat. No. 4,838,267, discloses melt extrusion of block copolymers of glycolide and p-dioxanone to form surgical filaments. The filaments are then treated with ethylene oxide in order to sterilize them. Also, Jamiolkowski et al., U.S. Pat. No. 4,889,119, discloses injection molding a polymer with high lactide content and a polymer with a high glycolide content to form a surgical fastener. The fastener is then packaged and sterilized by conventional means. The low temperature and low humidity conditions of ethylene oxide treatment do not appear to present problems to the mechanical properties. However, toxic residues and possible byproducts must be removed before implantation, otherwise an inflamatory response may occur.
Electron beam or gamma radiation is effective in sterilizing bulk materials at low temperatures without chemical residues. However, chain scission of the biodegradable polymers by the high-energy radiation causes pre-degradation and a subsequent reduction in mechanical strength of the resultant implant. Shalaby et al., U.S. Pat. No. 4,190,720, discloses a polymeric material that is biodegradable and sterilizable with radiation. The polymeric material, though, is sterilized in a separate step following the formation of the implant.
Van den Berg, U.S. Pat. No. 5,225,129, discloses reaction injection molding cyclic monomers and catalysts to form a biodegradable polymeric material. Van den Berg further discloses the possibility of lining the mold with a flexible bag into which the mixture is injected and which, if sealed prior to polymerization, may form a sterile implant. However, the bag is needed in order to prepare a sterile implant.
Therefore, there remains a need for a method for making biodegradable polymeric implants that do not require post-formation sterilization of the implant, as well as a method in which a lining is not needed in the mold in order to form the sterile biodegradable implant. In addition, there is a need for a method in which sterile biodegradable polymeric implants can be manufactured in a one-step polymerization process from inexpensive raw materials. There is a further need for a method of producing high molecular weight implants with great detail and in which the crystallinity of the polymer is easily controlled.
There is also a need for a method in which sterile biodegradable implants made from block copolymers and sterile biodegradable implants made from cross-linked polymers can be manufactured in an inexpensive one-step manufacturing process.
Applicant has unexpectedly discovered a novel method of making a biodegradable polymeric implant comprising the steps of:
a) mixing at least one monomer and at least one telechelic polymer with at least one catalyst to form a polymerization mixture;
b) injecting said polymerization mixture into a mold in the shape of the desired implant; and
c) polymerizing said polymerization mixture in said mold to form a biodegradable polymeric implant.
Another embodiment of the inventive subject matter is a method of making a biodegradable polymeric implant comprising the steps of:
a) mixing at least one crosslinking agent and at least one telechelic polymer with at least one catalyst to form a crosslinkable polymerization mixture;
b) injecting said crosslinkable polymerization mixture into a mold in the shape of the desired implant; and
c) crosslinking said polymerization mixture in said mold to form a crosslinked biodegradable polymeric implant.
A further embodiment of the inventive subject matter is a method of making a biodegradable polymeric implant comprising the steps of:
a) aseptically mixing at least one monomer and at least one telechelic polymer with at least one catalyst to form a polymerization mixture;
b) aseptically injecting said polymerization mixture into an unlined sterile mold in the shape of the desired implant; and
c) polymerizing said polymerization mixture in said unlined sterile mold to form a sterile biodegradable polymeric implant.
In a still further embodiment of the present inventive process, the method is carried out aseptically and the biodegradable implant formed is sterile.
The present inventive subject matter is also drawn to the polymeric implants produced by the method. The polymeric implants may exhibit high tensile strengths and high inherent viscosities.
In addition to the implants exhibiting high tensile strengths and inherent viscosities, an advantage of the present inventive method is that biodegradable polymeric implants can be manufactured in a one-step polymerization process from inexpensive raw materials without the use of a liner in the mold. Another advantage of the present inventive method is that high molecular weight parts can be made with greater detail than with conventional injection molding because the polymerization mixture has a low viscosity when it enters the mold. A further advantage of the present inventive subject matter is that the crystallinity, biodegradation, chemical, physical and mechanical properties can be more easily controlled by the use of the telechelic polymers and/or cross-linking agents.